Glucocorticoids are known to promote the development of
metabolic syndrome through the modulation of both feeding pathways and metabolic processes; however, the precise mechanisms of these effects are not well-understood. Recent evidence shows that
glucocorticoids possess the ability to increase
endocannabinoid signaling, which is known to regulate appetite, energy balance, and metabolic processes through both central and peripheral pathways. The aim of this study was to determine the role of
endocannabinoid signaling in
glucocorticoid-mediated
obesity and
metabolic syndrome. Using a mouse model of excess
corticosterone exposure, we found that the ability of
glucocorticoids to increase adiposity,
weight gain, hormonal dysregulation, hepatic steatosis, and
dyslipidemia was reduced or reversed in mice lacking the
cannabinoid CB1 receptor as well as mice treated with the global
CB1 receptor antagonist
AM251. Similarly, a neutral, peripherally restricted
CB1 receptor antagonist (
AM6545) was able to attenuate the metabolic phenotype caused by chronic
corticosterone, suggesting a peripheral mechanism for these effects. Biochemical analyses showed that chronic excess
glucocorticoid exposure produced a significant increase in hepatic and circulating levels of the
endocannabinoid anandamide, whereas no effect was observed in the hypothalamus. To test the role of the liver, specific and exclusive deletion of hepatic
CB1 receptor resulted in a rescue of the dyslipidemic effects of
glucocorticoid exposure, while not affecting the
obesity phenotype or the elevations in
insulin and
leptin. Together, these data indicate that
glucocorticoids recruit peripheral
endocannabinoid signaling to promote metabolic dysregulation, with hepatic
endocannabinoid signaling being especially important for changes in lipid metabolism.